The mechanisms by which tissue morphogenesis initiates from the gut endoderm are not well defined. Although genetic methods have yet to provide much insight into hepatic specification and subsequent cell interactions, experiments with transplanted tissues have revealed more information. Hepatocytes develop from the endoderm lining the presumptive ventral foregut, near the developing heart. At about 9 days gestation in the mouse, foregut endoderm in contact with cardiac mesoderm proliferates more rapidly, and first α-fetoprotein (AFP) and then serum albumin mRNAs become detectable by in situ hybridization (Shiojiri et al. 1991. Cancer Res. 51:2611-2620) By 9.5 days gestation, hepatic endodermal cells migrate into the more posterior mesenchyme of the septum transversum, where they begin to form the liver. Each tissue has its own architectural constraints on how the vascular system must integrate with functional aspects of an organ. To construct a vascular system that is specific for the needs of a particular organ, the development of the vascular system must be carefully coordinated with the development of the parenchymal cells. Assembly into a nascent organ may be regulated through interactions between parenchymal cells and vascular endothelial cells during organ morphogenesis. Understanding vascular development coordination with organogenesis will provide insights into future efforts to reconstitute organ systems for medical purposes and to generate tissue types in vitro for research, toxicological, and pharmaceutical applications.
Despite the clear importance of understanding these principles, very little is known about the earliest steps of vasculogenesis during organ development. Vasculogenesis refers to the earliest stages of vascular development, during which vascular endothelial cell precursors undergo differentiation and coalesce to form a network of primitive tubules (Risau, W. 1997. Nature 386: 671-674). This initial lattice, consisting purely of endothelial cells, is then remodeled by a process referred to as angiogenesis (Risau, W. 1997. Nature 386: 671-674), which involves the sprouting, branching, and differential growth of blood vessels to form the more mature vasculatures seen in the adult organs. Angiogenic vascular development also involves the sprouting and penetration of vessels into previously avascular regions of the embryo (Folkman, J. and D'Amore, P. A. 1996. Cell 87:1153-1155; Lindahl, et al. 1997. Science 277: 242-245). Mechanisms of vascular development during organogenesis, particularly of the liver, are unknown and vasculogenesis, angiogenesis, or both may possibly be involved.
It is known that close proximity to the cardiac mesoderm with the foregut endoderm causes the foregut endoderm to develop into the liver (LeDouarin, N. M. 1975, Med. Biol. 53, 427-455). This initial induction is accompanied by the activation of liver genes and enhanced proliferation of the newly specified hepatic cells (Gualdi et al. 1996; Jung et al. 1999). In a second step, these hepatic cells migrate and/or proliferate into the adjacent septum transversum, generating the liver bud. This morphogenetic transition, from hepatic endoderm to liver bud, represents the major defining moment in converting a simple epithelium to a complex structure that establishes the foundation for organogenesis. Although it is known that mesenchyme cells in the septum transversum promote this transition (LeDouarin, N. M. 1975. Med. Biol. 53, 427-455; Rossi, J. M., Dunn, N. R., Hogan, B. L. M., and Zaret, K. S. 2001, Genes Dev. 15:1998-2009) the potential role of other cell types is unknown.